Mild Cognitive Impairment: a Prospective Community Study. Mild Cognitive Impairment (MCI) is the cognitive state intermediate between normal aging and dementia. Multiple terms, definitions, and criterion sets exist for MCI. In specialty clinical settings, MCI almost uniformly progresses to dementia at a high rate, and is assumed to represent prodromal dementia. In community studies, MCI is a more heterogeneous state with less elevated risk of progression to dementia, and with substantial proportions remaining only mildly impaired or even reverting to normal cognition. A better understanding is needed of who will and will not progress from MCI to dementia, so that diagnostic criteria can be based on predictive validity in the community at large, and so that individuals can be more appropriately targeted for prevention and early intervention. This application is for renewal of a new study of a cohort randomly selected from a community in Western PA. In 2008, the cohort completed recruitment of 2036 individuals aged 65+, and the majority of them have had APOE genotyping. We conduct annual followup assessments in overlapping 2-year cycles. This study was designed de novo to focus on MCI rather than on the more severe impairments typical of dementia. The assessment protocol allows the application of many extant classification systems and criterion sets for MCI, thus allowing their predictive values for dementia to be compared during followup. Besides the standard criteria, we have also developed reliable cognitive classifications relative to normative data from our cohort, and a novel web-based approach to expert diagnostic consensus. Relevant clinical and biological measures are assessed as covariates and predictors. The primary outcome measure is progression to dementia; we also examine longitudinal change measures in clinical dementia rating, individual cognitive domains, functional impairment, and other assessments. We now propose to follow the cohort for a further five years, so that sufficient individuals will undergo these changes to power the key analyses predicting progression to dementia from MCI. New measures include structural MRI brain imaging in 250 individuals to determine the extent to which measures of cortical and regional atrophy and white matter hyperintensities improve prediction of dementia in this community sample; assays of 6 vascular and inflammatory markers in stored serum, and genotyping for 13 new SNPs associated with Alzheimer's disease and stroke in all stored DNA. These new measures reflect an expanded emphasis on vascular risk factors. Continued followup of this well- characterized aging cohort will improve understanding of the heterogeneity of MCI in the population at large, and help identify reliable predictors of the outcomes of MCI.